1. Field of the Invention
This invention relates to pharmaceutical compositions containing certain diarylimidazole derivatives which selectively bind to human NPY receptors. Some of such diarylimidazoles are believed to be novel. The invention further relates to the use of such compounds in treating feeding disorders such as obesity and bulimia as well as certain cardiovascular diseases such as essential hypertension.
2. Prior Art
Neuropeptides known as Neuropeptide Y (NPY) are believed to have a role in a variety of functions in the body and in particular have been associated with stimulation of appetite but also to effect anxiolysis and regulation of coronary tone. Such compounds bind to a number of different receptor sites. U.S. Pat. No. 5,571,695 (Selbie et al.) describes the genomic DNA sequences that code for the Y-1 receptor. U.S. Pat. No. 5,554,621 (Poindexter et al.) describes certain 4-phenyl dihydropyridines that are NPY antagonists and noted the existence of at least five receptor subtypes for NPY. U.S. Pat. No. 5,545,549 (Gerald et al) describes the human Y2 receptor and the DNA coding for it. U.S. Pat. No. 5,516,653 (Bard et al.) describes the human Y4 receptor and the DNA coding for it. U.S. Pat. No. 5,602,024 (Gerald et al) describes the human Y5 receptor and the DNA coding for it. It states that this receptor seems to be the most significant for appetite stimulation.
Many diarylimidazoles are known for a variety of uses. For example, European Patent Publication 627499 (Shikoku Chemicals Corporation) and its United States equivalent, U.S. Pat. No. 5,498,301 (Hirao) describe the use of 2,4-diphenylimidazole and 2,4-diphenyl-5-methyl imidazoles as water based surface treating agents for use on copper surfaces and compares their activity to that of 2,4,5-triphenylimidazole. The 2-phenyl group may be substituted by alkyl or halo groups and the 4-phenyl group by alkyl, halo, alkoxy, di-loweralkylamino, cyano or nitro groups. Specific compounds mentioned in the United States Patent include 2-phenyl-4-(4-chlorophenyl)imidazole, 2-phenyl-4-(2,4-dichlorophenyl)imidazole, 2-phenyl-4-(4-bromophenyl)imidazole, 2-phenyl-4-(2-tolyl)imidazole, 2-phenyl-4-xylylimidazole, 2-(4-chlorophenyl)-4-phenylimidazole, 2-(4-bromophenyl)-4-phenylimidazole, 2-(2,4-dichlorophenyl)-4-phenylimidazole, 2-(4-tolyl)-4-phenylimidazole, 2-(4-methoxyphenyl)-4-phenylimidazole, 2-(4-dimethylaminophenyl)-4-phenylimidazole, 2-(4-cyanophenyl)-4-phenylimidazole, 2-(3-nitrophenyl)-4-phenylimidazole, 2-(2,4-xylyl)-4-phenylimidazole, 2-(4-chlorophenyl)-4-(4-chlorophenyl)imidazole, 2-(2,4-dichlorophenyl)-4-(2-tolyl)imidazole, 2-(2-bromophenyl)-4-(2,3-xylyl)imidazole, 2-(4-ethyl phenyl)-4-(2-chlorophenyl)imidazole, 2-(2-ethoxyphenyl)-4-(4-bromophenyl)imidazole, 2-(2-cyanophenyl)-4(4-tolyl)imidazole, 2-(3-nitrophenyl)-4-(2,3-dichlorophenyl)imidazole, 2-(4-diethylaminophenyl)-4-(4-flurophenyl)imidazole, 2-(4-chlorophenyl)-4-phenyl-5-methylimidazole, 2-(4-tolyl)-4-phenyl-5-methylimidazole, 2-(2,4-dichlorophenyl)-4-phenyl-5-methylimidazole, 2-(2,3-xylyl)-4-phenyl-5-methylimidazole, 2-(4-methoxyphenyl)-4-phenyl-5-methylimidazole, 2-(4-dimethylaminophenyl)-4-phenyl-5-methylimidazole, 2-(2-nitrophenyl)-4-phenyl-5-methylimidazole, 2-(3-cyanophenyl)-4-(4-chlorophenyl)-5-methylimidazole, 2-(2-nitrophenyl)-4-phenyl-5-methylimidazole, 2-(3-cyanophenyl)-4-(4-chlorophenyl)-5-methylimidazole.
PCT Publication WO 95/04274 (Nippon Soda Co. Ltd.) describes the use of a wide range of imidazoles for pest control including 2-(optionally halogenated)phenyl-4-(optionally halogenated) phenylimidazoles.
Suzuki et al. in Chem. Pharm. Bull (1986) 34, 3111-20 describe the synthesis of 2-aryl-4-(3-thienyl)imidazole derivatives of use as antiinflamatory agents.
U.S. Pat. No. 5,017,467 describes 2,4-di(2-substituted aminophenyl) imidazoles wherein the 5 position is optionally substituted by a group capable of being split off by reaction with an oxidized product of a color developing agent for use as a cyan coupler in photography.
East German patent publication 299059 (Chemical Abstracts 117:131199) describes 2-(2-hydroxyphenyl)-4-substituted imidazoles wherein the substituent in the 4 position may be an optionally substituted phenyl group and the 5 position may be substituted by a phenyl or alkyl group.
East German patent publication 297816 (Chemical Abstracts 116:214504) describes 2-arylimidazole compounds wherein the 4 or 5 positions may have aryl substituents of use as lipoxygenase inhibitors.
German Patent Publication 3917677 (Chemical Abstracts 115:25542) describes 2-(4-hydroxy-3,5-di-tert.-butyl)phenyl-4-(4-dialkylamino)phenylimidazoles of use as chromogenic substrates in analytical redox reactions. The 4-phenyl group and the 5 position of the imidazole ring may be further substituted by alkyl groups.
German Patent Publication 3411997 (Chemical Abstracts 104:145136) describes compounds of use as redox indicators including 2-(substituted phenyl)-4-(substituted phenyl) imidazoles.
Soviet Patent Publication 1051076 (Chemical Abstracts 101:90924) describes 2-phenyl-4-(phenyl or p-tolyl)imidazoles which may be methyl- or phenyl-substituted in the 5 position.
European Patent Publication 0131973 (Instituto de Angeli S. p. A.) describes the use of certain aryl imidazoles, including 2-phenyl-4-(4-nitro-phenyl)-1H-imidazole and 2-phenyl-4-(4-amino-phenyl)-1-imidazole as intermediates in the production of amidines useful as H.sub.2 receptor blocking agents.
U.S. Pat. Nos. 4,757,124 and 4,758,639 (Koyangi et al ) describe the use of inter alia 2,4-diphenylimidazole for prevention of scaling of the walls of a polymerization vessel used in the production of vinyl polymers.
Other compounds found in the course of database searches include: 4-(2,4-dichlorophenyl)-2-phenyl-5-methylimidazole; 2,4-bis-(2,4-dichlorophenyl)-imidazole (C.A. Registry No 197514-18-4); 2-(4-methoxyphenyl)-2-(2-aminophenyl) imidazole (C.A. Registry No 197011-25-9); 2-(4-methoxyphenyl)-2-(2-trifluoromethylphenyl)imidazole (C.A. Registry No 174356-09-3); 4-(2-ethylaminophenyl)-2-phenylimidazole (C.A. Registry 170448-20-1); N-[2-(2-phenyl-1H-imidazol-yl)-phenyl]acetamide (C.A. Registry 162706-94-7); 2-(4-chlorophenyl)-2-(3-trifluoromethylphenyl)imidazole (C.A. Registry 162701-76-0); N-[4-[2-(2-hydroxyphenyl)-1H-imidazol-yl]phenyl]acetamide (C. A. Registry 138500-29-5) and its methoxy homolog (C. A. Registry 138500-28-4); several 2-phenylimidazoles wherein the 4 position is substituted by a 3,3-dimethyl-2H-indole-2-one group (C. A. Registry Nos 135466-37-4, 135466-36-3; 135437-73-9; 135437-72-8; 135437-71-7; 135437-68-2; 135437-66-0; 135437-65-9; 135437-64-8; 135437-63-7; 135437-62-6; 135437-61-5; 135437-60-4 and 135437-59-1); analogous 2(1H)-3,4-dihydroquinolones (C.A. Registry Nos 135437-70-6 and 135437-67-1), 2,4-bis-(2-aminophenyl)-imidazole (C.A. Registry No 131623-81-9); 4-(4-hydroxyphenyl)-2-phenylimidazole (C.A. Registry No 111273-30-4); 2,4-bis(4-phenoxyphenyl)imidazole (C.A. Registry 107783-02-8); 2,4-bis(bi-phenyl-4-yl)imidazole (C.A. Registry 106304-01-2); 4-(2-phenyl-1H-imidazol-4-yl)benzeneamine (C.A. Registry No.96139-68-3); various 2-(2-hydroxyphenyl) 4-(possibly substituted) phenylimidazoles having methyl, ethyl, butyl or phenyl substituents in the 5-position; and a number of more complicated structures.